Acute or chronic neuronal injury can lead to cell death and degeneration in stroke or neurodegenerative diseases. A number of animal models have been developed to study these diseases but in most cases, animals have to be sacrificed to gain information on disease severity or to study pathogenic pathways. This is in contrast to many peripheral diseases where disease markers can be more easily measured in the blood or biopsies can be obtained without interfering dramatically with the disease. Therefore, new methods are necessary to study disease progression or cellular changes in the brain noninvasively. Bioluminescence imaging in living animals has recently been used to monitor and quantitate gene activity and disease progression in peripheral organs with great success. Although, this imaging modality lacks high resolution and cannot be used at present to localize signals with high accuracy, it is quantitative and can faithfully report gene activation if appropriate fusion gene constructs are used. Here we propose to use bioluminescence imaging in transgenic mice that harbor an injury-responsive Lucifer's reporter gene to assess neuronal injury or use mice that express luciferase at high levels in neurons to quantitate cell number. Strong preliminary data indicate that we can indeed collect photons that correlate with reporter gene activity from injured brains of living mice. We propose to use these mice, which carry a reporter gene responsive to the TGF-beta signaling pathway, to optimize non-invasive bioluminescence imaging of the brain and to try to quantitate neuronal injury non-invasively in two acute models of brain injury using bioluminescence imaging (Specific Aim 1}. We also propose to engineer related mice that express luciferase and YFP constitutively at high levels in defined groups of neurons to try to correlate bioluminescence signals in living mice with neuronal cell number (Specific Aim 2). If we are successful, our studies will demonstrate feasibility of using non-invasive bioluminescence imaging to measure gene activity in the brain and to use such measurements as indicators of pathological or physiological processes in individual mice. These, and other reporter mice could also be used to screen drugs for efficacy to interfere with or activate specific signaling pathways in living mice and to assess drug availability in the brain.